BACKGROUND: The utility of antineutrophil cytoplasmic antibody (ANCA) levels to guide the management of patients with Wegener granulomatosis remains controversial. OBJECTIVE: To determine whether pro-proteinase 3 (PR3)-ANCA levels are a better measure of disease activity than mature-PR3-ANCA levels, whether decreases in either level are associated with shorter time to remission, and whether increases are followed by relapse. DESIGN: Prospective, observational cohort study. SETTING: 8 United States medical centers that participated in a treatment trial for Wegener granulomatosis. PATIENTS: 156 patients with Wegener granulomatosis enrolled during periods of active disease. MEASUREMENTS: PR3-ANCA levels (by capture enzyme-linked immunosorbent assay) and disease activity (by the Birmingham Vasculitis Activity Score for Wegener granulomatosis). RESULTS: The ANCA levels were only weakly associated with disease activity across patients. The longitudinal association within patients was stronger, but changes in ANCA levels explained less than 10% of the variation in disease activity. Decreases in mature- and pro-PR3-ANCA levels were not statistically significantly associated with shorter time to remission, and increases in mature-PR3-ANCA levels (adjusted hazard ratio, 0.8 [95% CI, 0.4 to 1.9]; P = 0.67) and pro-PR3-ANCA levels (adjusted hazard ratio, 1.0 [CI, 0.5 to 2.1]; P = 0.99) were not associated with relapse. The proportion of patients who had relapse within 1 year of an increase in PR3-ANCA levels was 40% for mature-PR3 (CI, 18% to 56%) and 43% for pro-PR3 (CI, 22% to 58%). LIMITATIONS: Samples were collected approximately every 3 months. Sensitivity and specificity of ANCA levels for detecting remission and relapse could not be calculated because each patient had different follow-up times. CONCLUSION: Pro-PR3-ANCA is no better than mature-PR3-ANCA as a measure of Wegener granulomatosis activity. Decreases in PR3-ANCA levels are not associated with shorter time to remission, and increases are not associated with relapse. These findings suggest that ANCA levels cannot be used to guide immunosuppressive therapy.